Browsing by Author "Guazz, Milena"

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    Structural mapping of GABRB3 variants reveals genotype-phenotype correlations
    (2021) Johannesen, Katrine; Iqba, Sumaiya; Guazz, Milena; Mohammadi, Nazanin; Pérez, Eduardo; Schaefer, Elise; De Saint Martin, Anne; Abiwarde, Marie; McTague, Amy; Pons, Roser; Piton, Amelie; Kurian, Manju; Ambegaonkar, Gautam; Firth, Helen; Sanchis, Alba; Deprez, Marie; Jansen, Katrien; De Waele, Liesbeth; Briltra, Eva; Verbeek, Nienke; Van Kempen, Marjan; Fazeli, Walid; Striano, Pasquale; Zara, Federico; Visser, Gerhard; Braakman, Hilde; Haeusle, Martin; Elbracht, Miriam; Vahe, Ulvi; Smol, Thomas; Lemke, Johannes; Platzer, Konrad; Kennedy, Joanna; Martin, Karl; Ping, Billie; Smyth, Kimberly; Kaplan, Julie; Thomas, Morgan; Dewenter, Malin; Dinopoulos, Argirios; Campbell, Arthur; Lal, Dennis; Lederer, Damien; Liao, Vivian; Ahring, Philip; Møller, Rikke; Gardella, Elena
    Purpose: Pathogenic variants in GABRB3 have been associated with a spectrum of phenotypes from severe developmental disorders and epileptic encephalopathies to milder epilepsy syndromes and mild intellectual disability (ID). In this study, we analyzed a large cohort of individuals with GABRB3 variants to deepen the phenotypic understanding and investigate genotype-phenotype correlations. Methods: Through an international collaboration, we analyzed electro-clinical data of unpublished individuals with variants in GABRB3, and we reviewed previously published cases. All missense variants were mapped onto the 3-dimensional structure of the GABRB3 subunit, and clinical phenotypes associated with the different key structural domains were investigated. Results: We characterized 71 individuals with GABRB3 variants, including 22 novel subjects, expressing a wide spectrum of phenotypes. Interestingly, phenotypes correlated with structural locations of the variants. Generalized epilepsy, with a median age at onset of 12 months, and mild-to-moderate ID were associated with variants in the extracellular domain. Focal epilepsy with earlier onset (median: age 4 months) and severe ID were associated with variants in both the pore-lining helical transmembrane domain and the extracellular domain. Conclusion: These genotype-phenotype correlations will aid the genetic counseling and treatment of individuals affected by GABRB3-related disorders. Future studies may reveal whether functional differences underlie the phenotypic differences.

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